An inflammatory bowel disease is a generic term for enteropathy with inflammation, and mainly includes ulcerative colitis and Crohn's disease. The ulcerative colitis is a diffuse non-specific inflammatory disease where large bowel mucosa or submucosa is affected and erosion or ulcer is often formed. Clinical symptoms are mucous and bloody stools, abdominal pain, blood stools, watery stools, fever, lack of appetite, malevolence, emesis and the like. As agents for treating the ulcerative colitis, salazosulfapyridine, adrenal cortex steroids, immunosuppressants, 5-aminosalicylic acid (5-ASA) and the like are used, but it can not be said that these agents are enough to treat the ulcerative colitis.
Crohn's disease is an idiopathic chronic enteritis of unknown cause, and exhibits non-specific inflammatory symptoms in intestines from a small intestine to a large intestine. Its lesions are composed of granulomatous lesions with fibrosis and ulcer, and it is likely that the lesions appear in all gastrointestinal area from an oral cavity to an anus. The clinical symptoms of Crohn's disease include abdominal pain, general malaise, diarrhea, melena, occult blood positive, fever, weight loss, anemia, ileus symptom, abdominal tumor, malevolence, emesis and peritonitis symptom. Crohn's disease simultaneously causes various gastrointestinal and parenteral symptoms, e.g., intestinal stenosis, intestinal perforation, abdominal abscess and heavy hemorrhage which are serious conditions, in addition to nutritional disorder, and often requires procedures such as intestinal surgery. In Japan, a high calorie infusion or an enteral nutrition is performed for the purpose of improving the nutritional condition. In the high calorie infusion, a risk of bacterial translocation is increased. Thus, particularly for a long term, the enteral nutrition is performed. In addition, the therapy by an agent has been attempted. In the drug therapy, salazosulfapyridine, metronidazole, adrenal cortex steroids, immunosuppressants, 5-aminosalicylic acid (5-ASA) and the like are administered. Recently, an anti-TNF antibody has begun to be administered clinically. However, it can be said that the administration of these agents is insufficient yet for treating the Crohn's disease.
TNF-α is an inflammatory cytokine produced by macrophages, macrophage lineage cells (Kupper cells), neutrophils, basophils, eosinophils, lymphocytes, NK cells, LAK cells, mast cells, bone marrow cells, fibroblasts, astrocytes, keratinocytes and the like, and has been recently demonstrated to be deeply involved in pathogenesis of many diseases including Crohn's disease. Therefore, it is believed that if the action of TNF-α can be inhibited, it becomes possible to treat those diseases. Currently, steroidal hormone agents and non-steroidal anti-inflammatory agents are applied to some inflammatory diseases. However, they have diverse action points and do not have an inhibitory action specific for TNF-α. Thus, it is likely to elicit harmful side effects. Particularly, the side effect of the steroid agent has become a medical problem. Furthermore, the treatment using an anti-TNF-α antibody and a soluble TNF-α receptor which are peptide macromolecules gives good clinical results in chronic rheumatoid arthritis and Crohn's disease, but sometimes induces serious infectious diseases including tuberculosis and sepsis, and deterioration of demyelinating disease. Occurrence of malignant tumors has been also reported. Additionally, the formation of a neutralization antibody has been reported, and thus they can not be said to be sufficient.